Acylthiomethyl esters of cephalosporins

ABSTRACT

WHEREIN R1 is tetrazolylmethyl or (lower alkyl)tetrazolylmethyl; R2 is hydrogen or lower alkyl; R3 is lower alkyl; and X is thiadiazolylthio or (lower alkyl)thiadiazolylthio. They are useful as antibacterial agents.   New acylthiomethyl esters of cephalosporins have the formula

United States Paten [1 1 Breuer 1451 Dec. 30, 1975 [54] ACYLTHIOMETHYLESTERS OF CEPHALOSPORINS [75] Inventor: Hermann Breuer,Regensburg,

Germany [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: 061. 21, 1974 21 Appl. No.: 516,566

Related US. Application Data [63] Continuation-impart of Ser. No.277,700, Aug. 3,

1972, Pat. No. 3,860,591.

Primary Examiner-Nicholas S. Rizzo Attorney, Agent, or Firm-Lawrence S.Levinson; Merle J. Smith 1 57 ABSTRACT New acylthiomethyl esters ofcephalosporins have the formula COO-CH- S--COR wherein R istetrazolylmethyl or (lower a1kyl)tetrazolylmethyl; R is hydrogen orlower alkyl; R is lower alkyl; and X is thiadiazolylthio or (loweralkyl)- thiadiazolylthio- They are useful as antibacterial agents.

9 Claims, No Drawings ACYLTHIOMETHYL ESTERS OF I CEPHALOSPORINS I Thisapplication is a continuation-in-part of application Ser. No. 277,700,filed Augn3, 19 72, US. Pat. 3,860,591, issued Jan. 14, 1975'.

BACKGROUND OF THE INVENTION It is known that many cephalosporins areeither not absorbed or not readily absorbed in the gastrointestinaltract, 7-(2-thienylacetamido )cephalosporanic acid, for example. Suchcompounds are usually administered parenterally in order to achieve highserum' concentrations. It is therefore advantageous to have derivativesof cephalosporins a high percentage of which are ab- SUMMARY OF THEINVENTION This invention relates to new acylthiomethyl esters ofcephalosporins having the formula R is hydrogen, lower alkyl,cycloalkylmethyl, like cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclohexylmethyl, cyeloalkenylmethyl,monounsaturated cycloaliphatics like the foregoing cycloalkylmethylgroups, cycloalkadienylmethyl like cyclopentadienylmethyl orcyclohexadienylmethyl, aryloxymethyl like phenoxymethyl, aralkyl, e.g.,phenyl-lower alkyl or the same groups with simple substituents on thephenyl, cyanomethyl, azidomethyl, and certain heterocyclic groups likefuryimethyl, thienylmethyl, oxazolylmethyl, thiazolylmethyl,isoxazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl,tetrazolylmethyl, pyridylthiomethyl, and such groups simply substituted.Members of the foregoing groups substituted on the a-carbon atom with anamino, hydroxy, carboxy, ureido, lower alkanoylureido, sulfonylureido,sulfonyl or sulfonylamido groups are also included. R is hydrogen, loweralkyl, phenyl or phenyl-lower alkyl. R represents lower alkyl, loweralkenyl, aryl, halophenyl, benzhydryl or aralkyl groups such as thosedescribed above. X is hydrogen, h ydroxy, lower a lkanoyloxy, aroyloxy,lower alkoxy, aralkanoyloxy, the radical of a nitrogen base such asalkylamines or aralkylamines, quaternary ammonium radicals likepyridinium, quinolinium, picolinium and the like, lower alkyladditionsalts which are also within the scope of the invention.

The preferred members of the group are those wherein R is benzyl,phenoxymethyl, a-substituted benzyl, especially wherein thea-substituent is amino, hydroxy, carboxy or ureido, thienylmethyl, anda-substitu ted thienylmethyl especially wherein the a-substituent isamino, hydroxy, carboxy or ureido, pyridylthiomethyl, azidomethyl orcyanomethyl, R is hydrogen, lower alkyl, especially methyl, phenyl orphenyllower alkyl, especially benzyl, R is lower alkyl, especiallymethyl, ethyl, propyl, N-butyl, t-butyl or 1,l-diethylpropyl, loweralkeny especially allyl, phenyl, chlorophenyl, phenyl-lower alkyl,especially benzyl, phenethyl or a-methylbenzyl, or benzhydryl, and X ishydrogen lower alkanoyloxy, especially acetoxy or propionyloxy,benzoyloxy, pyridinium, lower alkoxy, I especially methoxy, loweralkylthio, especially methylthio, thiatriazolylthio, thiadiazolylthio,oxazolylthio and the lower alkyl, especially methyl, substituted membersof the last two.

DETAILED DESCRIPTION OF THE INVENTION The various groups represented bythe symbols have the meanings defined below and these definitions areretained throughout this specification.

The .lower alkyl groups are straight or branched chain hydrocarbonradicals having one to eight carbons in the chain, forexample, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, amyl or thelike. The lower alkenyl groups are monounsaturated groups like thosefirst described, the two to four carbon members being preferred. I

,The aryl groups are .monocyclic carbocyclic aryl groups includingsimply substituted members. By way of illustration, this includesthephenyl ring and simply substituted phenyl containing one to threesubstitutents (preferably only one) such as the halogens (chlorine andbromine being preferred), lower alkyl groups such as those definedabove, lower alkoxy groups, (i.e., lower alkyl groups of the typedefined above attached to an oxygen), hydroxy, amino, carboxy and thelike. In the case of the last two named substituents there is preferablyonly one, especially in the para position of the phenyl.

The aralkyl groups include a monocyclic carbocyclic aryl group attachedto a lower alkyl group, both as defined above, benzyl being preferred.

The cyclo-lower alkyl groups are the alicyclics of three to six carbonatoms, e.g., cyclopropyl, cyclobut-yl, cyclopentyl and cyclohexyl;cyclopentyl and cyclohexyl are preferred. The cyclo-lower alkenyl groupsare the 4 to 6 carbons monounsaturated cyclic groups includingcyclobutene, cyclopenteneand cyclohexene.

The cycle-lower alkadiene groups are similarcyclic groups which have twodouble bonds, particularly cyclohexadienyl and especially1,4-cyclohexadienyl. All

' thiadiazolylmethyl,

of these are attached to a bridging methylene group.

The heterocyclic groups represented by R are the heterocyclic radicalsthienylmethyl, furylmethyl, ox azolylmethyl, isoxazolylmethyl,oxadiazolylmethyl,

tetrazolylmethyl and thiazolylmethyl, as well as these heterocyclicswith the substituents halo, lower alkyl (particularly methyl and ethyl),

lower alk'oxy (particularly methoxy and ethoxy) or phenyl, andthienylmethyl having amino, hydroxy, carboxy or ureido as ana-substituent.

' In addition, the R groups, especially those with a cyclic substituent,may be substituted on the a-carbon atom. These include hydroxy, amino,carboxy, ureido, lower alkanoylureido, sulfonylureido, sulfonyl orsulfonylamido.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented byX include the acyl group of acid esters. The lower alkanoyl radicals arethe acyl radicals oflower fatty acids containing alkyl radicals of thetype described above. The lower alkanoyloxy groups include, for example,acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups arederived from monocyclic carbocyclic aryl groups of the kind described.Similarly the aralkanoyloxy groups consist of monocyclic carbocyclicaryl and alkanoyloxy radicals of the type described. X also representsthe radical of an amine, e.g., an alkylamine like methylamine,ethylamine,.dimethylamine, triethylamine, aralkylamine likedibenzylamine, N,N'-dibenzylpyridinium, pyridinium, l-quinolinium,l-picolinium, etc. The lower alkylmercapto groups represented by Xinclude, for example, methylmercapto, ethylmercapto, propylmercapto andthe like. The mercapto group may in addition bear one of theheterocyclic radicals oxadiazolyl, thiadiazolyl, tetrazolyl orthiatriazolyl, and these heterocyclics may also bear a lower alkylgroup, preferably methyl.

The compounds described above are essentially neutral, when -R,,however, is a basic group, a-aminobenzyl for example, acid additionsalts of the conventional type are formed, e.g., hydrohalides like thehydrochloride, other inorganic acid salts like the sulfate, phosphate,organic salts like the citrate, benzenesulfonate, toluenesulfonate, etc.

The new compounds of this invention may be synthesized by severalmethods.

According to one method the carboxy group of a cephalosporin of theformula s R1-CO-NH( CH X COOH (III) ,-co-NH COOY is made to react with acompound of the formula R R R and X have the same meaning as above, Y isa cation, e.g., a metal cation such as the alkali metal cations sodiumand potassium, or the cation of a nitrogen base such as the ammoniumion, trialkylammonium ions, etc., and hal is a halogen, especiallychlorine or bromine.

This reaction is effected at a temperature of about 0 to 50C.,preferably in a suitable inert organic solvent such asdimethylformamide, dimethylacetamide, acetone, dioxane or the like.

The compounds of formulas Ill and V are produced by known methods [H.Bohme et al., Liebigs Annalen 623, 92-l02 (1959) for example, as shownin the following flow scheme, by reacting a thioacid of formula Vl withan aldehyde of formula Vll whereby the corresponding hydroxymethyl esterof the thioacid III is formed, this is halogenated, for example bytreatment with a phosphorus trihalide, like phosphorus tribromide, toobtain the corresponding halomethyl ester R;;COSH R CHO (VI) (VII)halogenation The synthesis of the new acylthiomethyl esters ofcephalosporins of formula I may also be effected from a-haloalkyl estersof cephalosporanic acid derivatives of the formula r-- N R COOCH-hul CHX The compound of formula VIII is reacted with a salt,

for example, an alkali metal salt, of a compound of CH X COCCH-S-CO-R ora salt thereof with a reactive derivative of the acid R,COOH. Suchderivatives include, for example, acid halides, acid anhydrides, mixedanhydrides of the acid with, for example, carboxylic acid monoesters,trimethylacetic acid or benzoic acid, acid azides, active esters such ascyanomethyl ester or p-nitrophenyl ester or active amides such asacylimidazoles.

The acid R COOH may also be reacted with a compound of formula IX in thepresence of a carbodiimide, for example, N,N'-dicyclohexylcarbodiimide,or an isoxazole salt such as N-ethyl-S-phenylisoxazolium- 3'-sulfonate,or 2-ethoxy-l,Z-dihydroquinoline-l-carboxylic acid ethyl ester.

The compounds of formula IX are also new, and may be produced, forexample, by the reaction of a compound of the formula COOY to 50C.,preferably about room temperature, in an inert solvent such asdimethylformamid'e.

The compounds of formula IX may also be produced from compounds offormula I, especially when R, is a selected substituent such as b enzylor phenoxymethyl, by converting-this particular compound .of formula Iwith phosphorus pentachloride under anhydrous conditions to an imidechlorideofthe formula Then, by treating the product of formula XI withcertain alcohols, e.g., methanol or isopropanol, and further with water,the product of formula IX optimally in the form of its salt, such as thehydrochloride or tosylate, is obtained. By forming the salt the moleculeis stabilized and more readily isolated.

Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in differentoptically active forms. The various -stereoisomeric forms as well as theracemic mixtures are within the scope of the invention.

The compounds of this invention have antibacterial activity against bothgram positive and gram negative organisms such as Staphylococcus aureus,Salmonella schattmuelleri, 'Pseudomonas aeruginosa, Proteus vulgaris,Escherichia; coli and Streptococcus pyrogenes. They may be used asantibacterial agents in a prophylactic manner, e.g., in'cleaning ordisinfecting compositions, or otherwise to combat infections due toorganisms such as those named above. They also show activity againstfungi like Candida albicans. For example, a compound of formula I or aphysiologically acceptable salt thereof may b'e-used in various animalspecies in an amount of about 3 to mg./kg., daily, orally orparenterally, preferably orally, in single or two to four divided dosesto treat infections of bacterial origin, e.g., 4.0 mg./kg. in mice.

Up to about 500 mg. of a compound of formula I or a physiologicallyacceptable salt thereof may be incorporated in an oral dosage form suchas tablets, capsules or elixirs or in an injectable form in a sterileaqueous vehicle prepared according to conventional pharmaceuticalpractice.

They may also be used in cleaning or disinfecting compositions, e.g.,for cleaning barns or dairy equipment, at a concentration of about 0.01to 0.5% by weight of such compounds admixed with, suspended or dissolvedin conventional inert dry or aqueous carriers for application by washingor spraying. They are also useful as nutritional supplements in animalfeeds.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale. Additional variations may beproduced in the same manner by appropriate substitution in the startingmaterial.

EXAMPLE 1 21.4 g. (0.05 mol.) of the potassium salt of 7-(phenylacetamido)cephalosporanic acid, 8.45 g. (0.05

'mol.) of (bromomethyl)acetylsulfide and 200 m1. of

The crude porduct is purified by dissolving in methylene chloride andthe solution is chromatographed in a silica gel column. The product iseluted from the column with a mixture comprising 2 parts of methylenechloride and 1 part tetrahydrofuran. After concentrating, there areobtained 12.8 g. of residue, which solidifies upon trituration withether. The product thus obtained, the (acetylthio)methyl ester of7(phenylacetamido)cephalosporanic acid, melts at 95l00.

The following additional products are made by the procedure of Example 1by substituting for the bromomethylsulfide the appropriately substitutedsulfide.

X f R CH 2 O l 2 COOCH-S COR 3 Example R R2 R3 X 2 0 cu CH3 ci-i,ci-i HCl 3 HO H H Cl ococu CI 7 NH 2 4 Q-cu -CHa ococ,H

l Cl "2 5 (H3O Q a CH2CH3 cH oco 7 Qt H 8 Qt" H NH-CO-NH NH-CONH2COCH-continued Example OCH:-

EH CH 7. A compound as in claim 6 wherein the lower alkyl group ismethyl.

8. A compound as in claim I wherein R is (l-loweralkyl-lH-tetrazol-S-yDmethyl, R is hydrogen, R is lower alkyl and X is(5-lower alkyl-1,3,4-thiadiazol-2- yl)thio.

9. A compound as in claim 8 wherein each lower alkyl group is methyl. 1

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R1 is tetrazolylmethyl.
 3. A compound as in claim 1 wherein X is (lower alkyl)thiadiazolylthio.
 4. A compound as in claim 1 wherein R1 is tetrazol-5-yl, R2 is hydrogen, R3 is lower alkyl and X is (5-lower alkyl-1,3,4-thiadiazol-2-yl)thio.
 5. A compound as in claim 4 wherein each lower alkyl group is methyl.
 6. A compound as in claim 1 wherein R1 is tetrazol-1-yl, R2 is hydrogen, R3 is lower alkyl and X is (1,3,4-thiadiazol-2-yl)thio.
 7. A compound as in claim 6 wherein the lower alkyl group is methyl.
 8. A compound as in claim 1 wherein R1 is (1-lower alkyl-1H-tetrazol-5-yl)methyl, R2 is hydrogen, R3 is lower alkyl and X is (5-lower alkyl-1,3,4-thiadiazol-2-yl)thio.
 9. A compound as in claim 8 wherein each lower alkyl group is methyl. 